The development of noninvasive markers to detect subclinical graft injury and to predict transplant outcome is a priority for the transplant community, but the value of individual assays for use in clinical decision- making is unknown. We hypothesize that multiple, complementary, noninvasive monitoring approaches will detect subclinical graft injury that will ultimately permit us to predict long-term outcome in human allografi recipients. To address this, we have assembled a consortium of investigators and institutions with expertise in renal and heart transplant recipients, in the design and implementation of immunosuppressive protocols, and in the study of noninvasive monitoring techniques. Our goal is to develop and test the efficacy of noninvasive markers as indicators of transplant outcome in the context of immunosuppression protocols designed to minimize toxicity to the transplant recipient. We propose two studies with accompanying specific aims. Study 1. Noninvasive monitoring to predict outcome in de novo kidney transplant recipients. De novo recipients of first renal allografts will be randomized to receive maintenance immunosuppression using 1) standard triple therapy, 2) calcineurin inhibitor avoidance therapy or 3) early steroid withdrawal therapy. 240 patients (80 per group) will be recruited over 3 yrs at 5 centers and followed for a minimum of 24 mos. A proposed panel of monitoring assays will be performed at predefined time points and the results will be correlated with defined endpoints. Study concept 2. Safely limiting long-term toxicity in stable allograft recipients through drug substitution/calcineurin inhibitor withdrawal. 160 stable kidney recipients, and 100 stable cardiac transplant recipients with a calculated GFR > 40 ml/ml, will be recruited from 3-5 centers between 6 mos and 3 yrs post-transplant and followed for 24 mos. Patients will be randomized to control therapy or to calcineurin inhibitor substitution. Monitoring assays will be performed at predefined time points and results of each assay individually and in combination will be correlated with defined endpoints. The results of the studies will provide new insight into the role of noninvasive markers as potential guides for the clinical care of transplant patients and will enhance insights into mechanisms of rejection. These findings from this work are a necessary prerequisite to the ultimate goal of using noninvasive markers to facilitate individualization of immunosuppression in organ transplant recipients.